The present invention relates to novel substituted phenoxyhydroxy amines and derivatives thereof useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are useful in the treatment of neurological disorders such as traumatic brain injury, stroke, migraine, acute and chronic pain, epilepsy, Parkinson's disease, Alzheimer's disease, amyotropic lateral sclerosis, multiple sclerosis, psychosis, and depression.
It is well-established that an accumulation of calcium (calcium overload) in the brain is seen after anoxia, ischemia, migraine, and other hyperactivity periods such as after epileptic convulsions. An uncontrolled high concentration of calcium in neurons of the central nervous system (CNS) is known to cause most of the degenerative changes connected with the above disease states. Therefore, compounds which block the calcium channels of brain cells will be useful in the treatment of neurological disorders such as brain injury, stroke, migraine, acute and chronic pain, epilepsy, Parkinson's disease, Alzheimer's disease, amyotropic lateral sclerosis, multiple sclerosis, and the neurodegeneration associated with the same.
Compounds which partially or completely block sodium or calcium channels will be useful for the treatment of the above disorders by indirectly or directly blocking the calcium influx into the CNS. L-channel antagonists such as nimodipine (Gelmers H. J., et al., New England Journal of Medicine, 318:203-207 (1988)) and dual sodium/calcium channel antagonists such as phenytoin (Kinouchi H., et al., Stroke, 21:1326-1330 (1990)) have demonstrated antiischemic and anticonvulsant activities in animal and clinical studies.
It is also known that N- and P-type calcium channels are involved with the regulation of neurotransmitter release. Subtype-specific neuronal calcium blockers are antinociceptive in rodent models of painful peripheral neuropathy. Voltage-sensitive calcium channel blockers prevent pain behavior elicited by tactile stimulation in animals with permanent peripheral nerve injuries. The calcium channel blocker, SNX-111, has demonstrated activity in several rodent models of acute and chronic pain (Bowersox S. S., et al., Drug News and Perspective, 7:261-268 (1994)). Enhanced neurotransmitter release of glutamate, aspartate glycine, dopamine, and serotonin may contribute to the etiology of many neurological disorders. Blockade of neurotransmitter release may, therefore, be useful in the treatment of pain, psychosis, Parkinsonism, depression, epilepsy, and other convulsive disorders.
Canadian Patent Application CA 2,043,216 discloses compounds of Formula III ##STR1## and of their salts with pharmaceutically acceptable acids and also of pharmaceutical preparations containing these compounds III for the production of a medicament for the prevention of and for the treatment of fungal diseases, the radicals in Formula III having the following meaning:
R(1) is H, (C.sub.1 -C.sub.3)-alkyl (straight-chain or branched), (C.sub.2 -C.sub.18)-alkenyl (straight-chain or branched, mono- or polyunsaturated), benzyl, [unsubstituted or mono- or polysubstituted by F, Cl, Br, CF.sub.3, (C.sub.1 -C.sub.4)-alkyl (straight-chain or branched), OCH.sub.3, O-phenyl or phenyl], C(O)-(C.sub.1 -C.sub.6)-alkyl (straight-chain or branched), or C(O)-phenyl, PA1 R(2) is H, (C.sub.1 -C.sub.18)-alkyl (straight-chain or branched), (C.sub.1 -C.sub.6)-alkloxy-(C.sub.1 -C.sub.6 )-alkyloxy (straight-chain or branched), (C.sub.1 -C.sub.6)-alkyloxyphenyl (straight-chain or branched), (C.sub.2 -C.sub.18)-alkenyl (straight-chain or branched, mono- or polyunsaturated), (C.sub.3 -C.sub.12)-cycloalkyl (mono-, bi-, or multicyclic, such as norbornyl, adamantyl, or decahydronaphthalenyl), phenyl-(C.sub.1 -C.sub.6)-alkyl (straight-chain or branched, the alkyl chain being unsubstituted or mono- or disubstituted by OH), phenyl-(C.sub.2 -C.sub.6)-alkenyl (straight-chain or branched, mono- or polyunsaturated), diphenyl-(C.sub.1 -C.sub.6)-alkyl (straight-chain or branched) or phenyl, the phenyl systems being unsubstituted or mono- or polysubstituted by substituents from the group comprising F, Cl, Br, (C.sub.1 .varies.C.sub.18)-alkyl (straight-chain or branched), (C.sub.2 -C.sub.20)-cycloalkyl, OH, SH, (C.sub.1 -C.sub.18)-alkoxy (straight-chain or branched), (C.sub.1 -C.sub.4)-alkylenedioxy (straight-chain or branched), dimethylaminoethoxy, (C.sub.1 -C.sub.4)-alkoxycarbonylmethoxy (straight-chain or branched), phenoxy, phenyl, benzyl, phenethyl, thiophenyl, and C.sub.2 F.sub.20+1 where n is equal to 1-6, or PA1 R(2) is an indol-3-yl-(C.sub.1 -C.sub.4)-alkyl radical (straight-chain or branched), thienyl, thienylmethyl, the thienyl radical being unsubstituted or substituted by F, Cl, (C.sub.1 -C.sub.4)-alkyl or O(C.sub.1 -C.sub.4)-alkyl (straight-chain or branched), PA1 R(3) is defined as R(2), R(2) and R(3) each having the same or a different meaning, or PA1 R(2) forms a --(CH.sub.2).sub.n -chain with R(3) where n is equal to 4-6, in which a CH.sub.2 group can be replaced by oxygen, sulfur or nitrogen, the additional nitrogen carrying a hydrogen atom, a CH.sub.3, phenyl, benzyl or a phenethyl group as a further bonding component, and PA1 A is (C.sub.1 -C.sub.18)-alkyl (straight-chain or branched), (C.sub.2 -C.sub.18)-alkenyl (straight-chain or branched, mono- or polyunsaturated) or a group of the Formula II ##STR2## in which the radicals R(4), R(5), and R(6) have the following meaning: R(4) is H, (C.sub.1 -C.sub.18)-alkyl (straight-chain or branched), (C.sub.2 -C.sub.18 -alkenyl (straight-chain or branched, mono- or polyunsaturated), (C.sub.3 -C.sub.20)-cycloalkyl, [mono-, bi-, or multicyclic, unsubstituted or mono- or disubstituted by (C.sub.1 -C.sub.4)-alkyl (straight-chain or branched), (C.sub.1 -C.sub.4)-alkoxy (straight-chain or branched), C.sub.2 F.sub.20+1 where n is equal to 1-4, F, Cl, Br, or OH], Y--(C.sub.1 -C.sub.20)-alkyl (straight-chain or branched), Y--(C.sub.2 -C.sub.18)-alkenyl (straight-chain or branched, mono- or polyunsaturated), Y--(C.sub.3 -C.sub.20)-cycloalkyl (mono-, bi-, or multicyclic, unsubstituted or substituted as indicated above), phenyl, Y-phenyl, phenyl-(C.sub.1 -C.sub.4)-alkyl (straight-chain or branched), phenyl-(C.sub.1 -C.sub.4)-alkoxy (straight-chain or branched), biphenylyl, F, Cl, Br, C.sub.2 F.sub.20+1 (where n is equal to 1-8), CCl.sub.3, YH, naphthyl, CH or NO.sub.2, the phenyl systems being unsubstituted or mono- or disubstituted by F, Cl, CF.sub.3, (C.sub.1 -C.sub.4)-alkyl (straight-chain or branched), or (C.sub.1 -C.sub.4)-alkoxy (straight-chain or branched), PA1 where Y is equal to oxygen or sulfur, SO or SO.sub.2, PA1 R(5) is defined as R(4), R(4) and R(5) being identical or different, or PA1 R(4) together with R(5) forms a (CH.sub.2).sub.p chain where p is equal to 3 or 4 in the case in which the substituents are bonded to adjacent positions on the phenyl ring, and PA1 R(6) is H, (C.sub.1 -C.sub.15)-alkyl (straight-chain or branched), (C.sub.2 -C.sub.15)-alkenyl (straight-chain or branched, mono- or polyunsaturated), Y--(C.sub.1 -C.sub.15)-alkyl (straight-chain or branched), Y--(C.sub.2 -C.sub.15)-alkenyl (straight-chain or branched, mono- or polyunsaturated), phenyl, Y-phenyl, benzyl, biphenylyl, F, Cl, Br, I, C.sub.2 F.sub.20+1 (where n is equal to 1-8), CCl.sub.3, naphthyl or YH, and PA1 X is oxygen or sulfur for use in the prevention and treatment of fungal diseases. PA1 R.sup.1 is ##STR4## wherein R.sup.2 and R.sup.3 are each the same or different and each is hydrogen, alkyl, alkoxy, benzyloxy, cycloalkyl, halogen, or trifluoromethyl, ##STR5## X is O or S; and isomers thereof; or a pharmaceutically acceptable salt thereof. PA1 R is methyl, arylalkyl, cyclohexylmethyl, or indol-3-ylmethyl; PA1 R.sup.1 is ##STR6## wherein R.sup.2 and R.sup.3 are each the same or different and each is alkyl, benzyloxy, cycloalkyl, or trifluoromethyl, ##STR7## X is O or S. PA1 R.sup.1 is ##STR9## wherein R.sup.2 and R.sup.3 are each the same or different and each is hydrogen, alkyl, alkoxy, benzyloxy, cycloalkyl, halogen, or trifluoromethyl, ##STR10## X is O or S with epichlorohydrin in a solvent such as, for example, 2-butanone and the like to afford a compound of Formula III wherein R.sup.1 and X are as defined above. Preferably, the reaction is carried out in 2-butanone.
However, the compounds disclosed in CA 2,043,216 do not specifically disclose or suggest the compounds of the present invention described hereinafter.